Identification of HTLV-I tax trans-activator mutants exhibiting novel transcriptional phenotypes.
The type I human T-cell leukemia virus (HTLV-I) encodes a 40-kD nuclear trans-regulatory protein termed Tax that transcriptionally activates the HTLV-I long terminal repeat (LTR), as well as select [corrected] cellular and heterologous viral promoters. Tax does not bind DNA specifically but, rather, acts in a more indirect manner. Tax activation of the HTLV-I LTR is mediated through constitutively expressed cellular factors that bind to cAMP response elements (CREs) present within the 21-bp enhancers of the LTR. In contrast, Tax transactivation of the interleukin-2 receptor-alpha gene (IL-2R alpha) and LTR of the type 1 human immunodeficiency virus (HIV-1) involves the induced nuclear expression of NF-kappa B. We now report the identification of missense mutations within the tax gene that functionally segregate these two pathways of trans-activation. Additionally, we demonstrate that the carboxyl terminus of the Tax protein, despite its acidic and predicted alpha-helical structure, is completely dispensable for trans-activation through either of these transcription factor pathways. Finally, we demonstrate that mutations within a putative zinc finger domain disrupt the nuclear localization of Tax and abolish trans-activation. These results demonstrate that Tax trans-activation of viral and cellular promoters involves at least two mechanisms of host transcription factor activation and suggest that this activation is likely mediated through distinct functional domains.
Smith
M R
MR
Howard Hughes Medical Institute, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
Greene
W C
WC
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004742:Enhancer Elements, Genetic; D005091:Exons; D005455:Fluorescent Antibody Technique; D016356:Gene Products, tax / Q000032:analysis / Q000235:genetics*; D016355:Genes, pX; D015368:Human T-lymphotropic virus 1 / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D012091:Repetitive Sequences, Nucleic Acid; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D016335:Zinc Fingers
D016356:Gene Products, tax